Abstract 1345: Chronic Renin-Angiotensin-Aldosterone System Inhibition Reduces Arrhythmogenic Vulnerability of the Aged Mouse Heart
Background Aging-induced cardiac fibrosis results in arrhythmia vulnerability of the aged RV of the mouse heart. The renin-angiotensin-aldosterone system (RAAS) governs myocardial collagen synthesis. We hypothesized that chronic RAAS inhibition limits fibrosis development and result in reduced arrhythmia vulnerability of the aged mouse heart.
Methods 124 Wildtype C57BL/6 Mice, aged 52 weeks, were treated for 36 weeks:
Aldosterone blocker, Eplerenone (E; 200mg/kg/d);
Angiotensin II receptor antagonist, Losartan (L; 10mg/kg/d);
co-treatment 2 and 3 (EL).
Epicardial activation mapping (208 sites, RV and LV) was performed on Langendorff perfused hearts (88 weeks). ERP was determined by premature stimulation. Arrhythmia inducibility was tested by 1–3 premature stimuli and burst pacing. Conduction velocity longitudinal and transversal (CVt) to fiber orientation and dispersion of conduction was determined during S1-S1 pacing (150 ms). Hearts were processed for Connexin 43 protein (Cx43; western blotting) and collagen (Sirius Red staining).
Results EP characteristics of LV were unaltered in treated groups. In contrast, in RV of E, L, and EL, CVt increased and anisotropic ratio (AR) decreased significantly compared to C. ERP and dispersion of conduction were unaltered. Anisotropic reentrant arrhythmias were induced in 12 of 23 C hearts (52%); 10 in RV only, 2 in both RV and LV. RV arrhythmogeneity was significantly reduced in E (22%), L (26%), and EL (16%), but unaltered in LV. Cx43 protein levels were increased and interstitial fibrosis significantly decreased in both RV and LV of all treated groups. Scattered patches of replacement fibrosis were found in 90% of C hearts (entire RV free wall; LV endo- and mid-myocardium), varying in severity and abundance, which were reduced in E (50%), L (56%), and EL (45%). A significant correlation was found between severity and abundance of patchy fibrosis and arrhythmia inducibility.
Conclusions Chronic RAAS inhibition limited aging-related development of interstitial fibrosis, and Cx43 reduction, resulting in increased CVt and decreased AR in RV. This, in concert with the reduced incidence of patchy fibrosis, decreased the RV susceptibility to reentrant arrhythmias of the aged mouse heart.